Protein kinases—enzymes phosphorylating proteins—play central role in cell signaling and cell division, and are therefore prominent therapeutic targets. Hundreds of protein kinases have been identified, differing in substrate specificity, the way of activation, and tissue occurrence or subcellular localization, wherein said protein kinases are members of multiple simultaneous pathways which may be independent or interlinked; consequently, it is difficult to target a specific enzyme involved in a certain pathological state.
Among the protein kinases, the super-family of mitogen activated protein kinases (MAPKs) seems to play a major role in signal transduction pathways. The members of the MAPKs family are involved in the regulation of a large variety of cellular processes, such as cell growth, differentiation, development, programmed cell death (apoptosis) and survival. ERKs (½) (extracellular signal-regulated kinases) are generally associated with cell proliferation and survival, while JNKs (c-Jun N-terminal kinases) and p38-MAPKs are responsible to cellular stress, such as hyperosmotic shock, metabolic stress or protein synthesis inhibitors, UV radiation, heat shock, cytokines and ischemia, all leading to apoptotic response. U.S. Pat. No. 6,495,582 discloses certain isoxazoles as inhibitors of ERKs, and their use for treating an ERK-mediated disease, whereas the recited disorders comprise nearly all existing diseases. U.S. Pat. No. 6,503,930 discloses novel pyrazoles and their use for treating the disorders mediated by p38, reciting the diseases related to inflammation. U.S. Pat. No. 6,130,235 discloses certain piperazines or piperidines inhibiting p38, and their use for treating a condition associated with p38 kinase.
An additional signaling pathway that plays a crucial role in the expression of stress-responsive genes and survival in a variety of cells and organs is the JAKs/STATs signaling pathway. STATs (signal transducers and activators of transcription) are a family of transcription factors that are activated by the JAK family of kinases. When cells encounter various extracellular ligands, such as interferons and EGF, the STATs promote rapid induction of genes.
Cardiovascular diseases and malignancies are the principal cause of death in the developed countries. Many protein kinases have been implicated in various aspects of cardiac pathologies and cancer pathogenesis. Cardiovascular diseases are characterized by diverse cellular abnormalities. These abnormalities may be stimulated by a variety of hormones and growth factors, whose signals are amplified by cascades involving protein kinases as PKCs and the MAPKs super-family. Recent evidence suggests that activation of MAPKs super-family plays a key role in the pathogenesis of various processes in the heart, e.g. in myocardial hypertrophy and its transition to heart failure, in ischemic and reperfusion injury, as well as in cardioprotection induced by preconditioning. Modulation of MAPKs activity may represent a potential therapeutic target providing protection on the myocardium by way of either inhibition of deleterious pathways and shifting the balance toward cell survival or by activation of pathways participating in the cardioprotective cascade. The JAKs/STATs signaling pathway was also found to participate in the ischemia/reperfusion process and the cardioprotection following preconditioning. However, the complexity of these systems lead to contradictory data and conclusions, and in some cases it is even unclear if the therapeutic goal is to inhibit or to activate a certain kinase. What seems to be needed most are new agents that could selectively inhibit detrimental pathways and activate the benign ones [e.g.: Vlahos C. J. et al.: Nature Reviews, Drug Discovery 2 (2003) 99-113; Bolli R. et al.: Trends Cardiovasc. Med. 13 (2003) 72-9].
It is therefore an object of this invention to provide compounds capable of signal transduction modulating protein kinases such as kinases from MAPKs family, JAKs/STATs and Akt for use as medicaments in treating cardiovascular diseases. Such medicament should, e.g., help in the survival of cardiomyocytes—“the good cells”, and should inhibit the proliferation of vascular smooth muscle (VSM) cells—“the bad cells”. An ideal compound would, for example, increase ERKs signaling pathway to induce cardioprotective functions and survival, and inhibit p38 and/or JNK/SAPK activation to reduce cardiomyocyte death, and further it would stimulate p38 and/or JNK/SAPK activation and inhibit ERKs signaling in said VSM cells; thus, the survival of cardiomyocytes would be enhanced, and the uncontrolled proliferation of VSM cells would be reduced in atherosclerosis, stenosis or resteriosis diseases. Enhancement of the ERKs signaling pathway and other survival pathways may be also beneficial for cardiomyocyte survival in diseases such as myocardial infarction.
The MAPKs family and the JAKs/STATs pathway may also offer new opportunities in development of novel selective anti-cancer drugs. Numerous solid tumors are known to express constitutive levels of phosphorylated ERK1 and ERK2 that activate variety of transcription factors. Mutation in Ras and Raf were also identified in a range of human tumors. Therefore, the Ras-Raf-MEK-ERKs signaling cascade may be an important target in cancer therapies [Hilger R. et al.: Onkologie 25(6) (2002) 511-8]. For some cancers, especially those of hematopoietic origin, the p38 and JNKs pathways may be targeted. Significant percentage of human tumors exhibits the constitutive activation of the MAPKs pathway [Hoshino, R. et al.: Oncogene 18(3) (1999) 813-22], suggesting that a single agent could concurrently exploit more than one of these processes, and potentially impair the tumor survival. Thus, therapeutic approaches to cancer treatment may involve slowing the tumor growth, inhibiting the invasion and metastasis, inducing tumor cell death, or promoting tumor differentiation. The STATs proteins are also known to participate in cellular transformation, tumorigenesis and oncogenesis. Subsequent work showed that in a number of tumor-derived cell lines, the STATs, particularly STAT3, are required to maintain a transformed phenotype. STATS is also commonly found to be constitutively activated in certain malignancies, especially leukemia and lymphomas. [Bromberg J.: JCI 109 (2002) 1139-42, Luo C. et al.: Drug Discovery Today 9 (2004) 268-75].
Therefore, the present invention further aims at providing drugs for treating malignancies by modulation the activity of protein kinases such as MAPKs family, JAKs/STATs and Akt through either inhibiting the deleterious pathways and shifting the balance toward the cell apoptosis, or by activating the pathways participating in the tumor differentiation.
It is an object of the invention to provide novel compounds capable of modulating protein kinase systems, the compounds being pyrrolidino-substituted 1,4-naphthoquinone derivatives.
Still another object of the present invention is to provide pyrrolidino-substituted 1,4-naphthoquinone derivatives capable of inhibiting or stimulating the MAPKs activity in cardiomyocytes, VSM cells, or malignant cells.
Other objects and advantages of present invention will appear as description proceeds.